Transition to Psychosis Associated With Prefrontal and Subcortical Dysfunction in Ultra High-Risk Individuals.
Schizophr Bull. 2012 Jan 30;
Authors: Allen P, Luigjes J, Howes OD, Egerton A, Hirao K, Valli I, Kambeitz J, Fusar-Poli P, Broome M, McGuire P
Abstract
Background:People at ultra high risk (UHR) of psychosis have an elevated risk of developing a psychotic disorder, but it is difficult to predict which individuals will make a transition to frank illness. We investigated whether functional magnetic resonance imaging (fMRI) in conjunction with a phonological fluency task at presentation could distinguish subjects who subsequently developed psychosis from those who did not.Methods:Sixty-five subjects (41 with an UHR and 24 healthy controls) were assessed at clinical presentation using fMRI, in conjunction with a verbal fluency task. [18F]-DOPA positron emission tomography (PET) data were also available in a subgroup of 21 UHR and 14 healthy controls subjects. UHR subjects were followed clinically for at least 2 years.Results:Compared with UHR subjects who did not become psychotic, UHR subjects who subsequently developed psychosis showed increased activation in bilateral prefrontal cortex (PFC), brainstem (midbrain/basilar pons), the left hippocampus, and greater midbrain-PFC connectivity. Furthermore, exploratory analysis of [18F]-DOPA PET data showed that transition to psychosis was associated with elevated dopaminergic function in the brainstem region.Conclusions:In people at high risk of psychosis, increased activation in a network of cortical and subcortical regions may predict the subsequent onset of illness. Functional neuroimaging, in conjunction with clinical assessment and other investigations, may facilitate the prediction of outcome in subjects who are vulnerable to psychosis.
PMID: 22290265 [PubMed - as supplied by publisher]
Introduction:Antipsychotic drugs exert antipsychotic effects by blocking dopamine D(2) receptors in the treatment of schizophrenia. However, effects of D(2) receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D(2) receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial.Methods:The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D(2) receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D(2) occupancy levels, on neurocognitive functions.Results:D(2) occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D(2) receptor occupancy level of >77%.Discussion:These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D(2) occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.
PMID: 22290266 [PubMed - as supplied by publisher]
Content and Quality of 10 000 Controlled Trials in Schizophrenia Over 60 Years.
Schizophr Bull. 2012 Jan 30;
Authors: Miyar J, Adams CE
Abstract
Objective:To carry out an up-to-date comprehensive survey of the content and quality of intervention trials relevant to the treatment of people with schizophrenia.Design:Data were extracted and analyzed from 10 000 trials on the Cochrane Schizophrenia Group’s Register.Main outcome measures:Source, type and date of publication, country of origin, language, size of trial, interventions, and outcome measures.Results:In the last decade, there has been a great increase in the number of trials relevant to schizophrenia and an improvement in the accessibility to reports. The number of trials per year is rising (currently ∼600/year) with China now producing 25% of the annual total. The number of reports of trials is increasing at an even greater rate due to multiple publications. Drug trials still dominate (83%) although an increasing proportion of studies are now evaluating psychological therapies (21%). Trials remain small (median 60 people) and often employ new nonvalidated outcomes scales (2194 different scales were employed with every fifth trial introducing a new rating instrument).Conclusions:A more collaborative, pragmatic, and patient-centered approach is necessary to produce larger schizophrenia trials. Wider consultation and careful consideration of all relevant perspectives would result in trials with greater clinical utility and direct value to people with the illness and their families or carers.
PMID: 22290267 [PubMed - as supplied by publisher]
NR4A2: Effects of an “Orphan” Receptor on Sustained Attention in a Schizophrenic Population.
Schizophr Bull. 2012 Jan 31;
Authors: Ancín I, Cabranes JA, Vázquez-Álvarez B, Santos JL, Sánchez-Morla E, Alaerts M, Del-Favero J, Barabash A
Abstract
NR4A2 (nuclear receptor subfamily 4 group A member 2) or Nurr1 is a transcription factor implied in the differentiation, maturation, and survival of dopaminergic neurons. It also has a role in the expression of several proteins that are necessary for the synthesis and regulation of dopamine (DA), such as tyrosine hidroxilase, dopamine transporter, vesicular monoamine transporter 2, and cRET. DA is an important neurotransmitter in attentional pathways. Our aim was to evaluate the influence of NR4A2 gene in the performance of schizophrenia (SZ) patients and healthy subjects on a sustained attention task. For this study, we collected 188 SZ subjects (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) and 100 control individuals. We genotyped 5 tag SNPs in NR4A2 gene: rs1150143 (C/G), rs1150144 (A/G), rs834830 (A/G), rs1466408 (T/A), and rs707132 (A/G). We also analyzed the influence of its haplotypes (frequency >5%). To examine sustained attention, all the individuals completed the Degraded Stimulus Continuous Performance Test. We evaluated “hits,” “reaction time,” “sensibility a,” and “false alarms.” In the schizophrenic group, recessive genotypes of rs1150143, rs1150144, rs834830, and rs707132 were associated with a worse performance. SZ subjects who carried GGGTG haplotype showed less hits (P < .004), lower sensibility a scores (P < .009), and a higher reaction time (P = .013). We observed a sex effect of the gene: genotype and haplotype associations were only present in the male group. We conclude that NR4A2 gene is involved in attentional deficits of SZ patients, modifying hits, sensibility a, and reaction time.
PMID: 22294735 [PubMed - as supplied by publisher]
Comparing Retrospective Reports to Real-Time/Real-Place Mobile Assessments in Individuals With Schizophrenia and a Nonclinical Comparison Group.
Schizophr Bull. 2012 Feb 1;
Authors: Ben-Zeev D, McHugo GJ, Xie H, Dobbins K, Young MA
Abstract
Retrospective reports are often used as the primary source of information for important diagnostic decisions, treatment, and clinical research. Whether such reports accurately represent individuals’ past experiences in the context of a serious mental illness such as schizophrenia is unclear. In the current study, 24 individuals with schizophrenia and 26 nonclinical participants used a mobile device to complete multiple real-time/real-place assessments daily, over 7 consecutive days. At the end of the week, participants were also asked to provide a retrospective report summarizing the same period. Comparison of the data captured by the 2 methods showed that participants from both groups retrospectively overestimated the intensity of negative and positive daily experiences. In the clinical group, overestimations for affect were greater than for psychotic symptoms, which were relatively comparable to their retrospective reports. In both samples, retrospective reports were more closely associated with the week’s average than the most intense or most recent ratings captured with a mobile device. Multilevel modeling revealed that much of the variability in weekly assessments was not explained by between-person differences and could not be captured by a single retrospective estimate. Based on the findings of this study, clinicians and researchers should be aware that while retrospective summary reports of the severity of certain symptoms compare relatively well with average momentary ratings, they are limited in their ability to capture variability in one’s affective or psychotic experiences over time.
PMID: 22302902 [PubMed - as supplied by publisher]
Report on the Inaugural Meeting of the International Consortium on Hallucination Research: A Clinical and Research Update and 16 Consensus-Set Goals for Future Research.
Schizophr Bull. 2012 Jan 5;
Authors: Waters F, Aleman A, Fernyhough C, Allen P
Abstract
This article presents a report on the first meeting of the International Consortium on Hallucination Research, which took place on September 13-14, 2011 at the Institute of Psychiatry, London. The first day of the meeting served to reflect on the current state of knowledge regarding auditory hallucinations in different diagnostic groups, based on the presentations from the phenomenology, cognition, emotion, electrophysiology, neurochemical, neuroimaging, genetics, treatment, and computational modeling working groups. The second day comprised a discussion forum where the most important and urgent questions for future research were identified. The meeting recognized that a lot has been achieved in auditory hallucination research but that much still remains to be done. Here, we outline the top 16 goals for research on auditory hallucinations, which cover topics of conceptual importance, academic and treatment issues, scientific rigor, and cross-disciplinary collaboration. Concerted and coordinated actions will be required to make substantial research progress.
PMID: 22223735 [PubMed - as supplied by publisher]
Expression of NPAS3 in the Human Cortex and Evidence of Its Posttranscriptional Regulation by miR-17 During Development, With Implications for Schizophrenia.
Schizophr Bull. 2012 Jan 6;
Authors: Wong J, Duncan CE, Beveridge NJ, Webster MJ, Cairns MJ, Shannon Weickert C
Abstract
NPAS3 is a developmentally important transcription factor that has been associated with psychiatric illness. Our aim is to better define the regulation of NPAS3 mRNA (messenger RNA) levels during normal human prefrontal cortical development and in schizophrenia. Utilizing postmortem tissue from 134 human brains, we assessed: 60 normal brains ranging in age from birth to adulthood, 37 chronic individuals with schizophrenia, and 37 matched controls. mRNA and microRNA (miRNA) expressions were measured by microarray and quantitative real-time PCR. Protein expression was measured by Western blotting. During human postnatal cortical development (neonate to adult), we found decreased NPAS3 mRNA yet increased NPAS3 protein expression, suggesting the involvement of posttranscriptional regulation. Through screening, we identified one NPAS-targeted miRNA (miR-17) that changed in a pattern consistent with the developmental regulation of NPAS3. Using luciferase reporter assays, we assessed the impact of miR-17 on NPAS3 translation and demonstrated that miR-17 alters NPAS3 biosynthesis by binding to the NPAS3 3′untranslated region (UTR). In schizophrenia prefrontal cortex, we found significant elevations in miR-17 expression. While NPAS3 mRNA was unaltered, reduced NPAS3 protein expression was detected in a subpopulation of people with schizophrenia. The reciprocal expression of NPAS3 mRNA and protein during postnatal development mediated by a schizophrenia-associated change in miR-17 suggests that there is complex control over NPAS3 synthesis in the human prefrontal cortex and that if NPAS3 is dysregulated in schizophrenia, it is not evident by large changes in NPAS3 expression. Further studies into how changes in NPAS3 or its miRNA regulator may influence the development of schizophrenia are warranted.
PMID: 22228753 [PubMed - as supplied by publisher]
Principal Components of Heritability From Neurocognitive Domains Differ Between Families With Schizophrenia and Control Subjects.
Schizophr Bull. 2012 Jan 10;
Authors: Wiener H, Klei L, Calkins M, Wood J, Nimgaonkar V, Gur R, Bradford LD, Richard J, Edwards N, Savage R, Kwentus J, Allen T, McEvoy J, Santos A, Gur R, Devlin B, Go R
Abstract
Objective: Various measures of neurocognitive function show mean differences among individuals with schizophrenia (SZ), their relatives, and population controls. We use eigenvector transformations that maximize heritability of multiple neurocognitive measures, namely principal components of heritability (PCH), and evaluate how they distribute in SZ families and controls. Methods: African-Americans with SZ or schizoaffective disorder (SZA) (n = 514), their relatives (n = 1092), and adult controls (n = 300) completed diagnostic interviews and computerized neurocognitive tests. PCH were estimated from 9 neurocognitive domains. Three PCH, PCH1-PCH3, were modeled to determine if status (SZ, relative, and control), other psychiatric covariates, and education were significant predictors of mean values. A small-scale linkage analysis was also conducted in a subset of the sample. Results: PCH1, PCH2, and PCH3 account for 72% of the genetic variance. PCH1 represents 8 of 9 neurocognitive domains, is most highly correlated with spatial processing and emotion recognition, and has unadjusted heritability of 68%. The means for PCH1 differ significantly among SZ, their relatives, and controls. PCH2, orthogonal to PCH1, is most closely correlated with working memory and has an unadjusted heritability of 45%. Mean PCH2 is different only between SZ families and controls. PCH3 apparently represents a heritable component of neurocognition similar across the 3 diagnostic groups. No significant linkage evidence to PCH1-PCH3 or individual neurocognitive measures was discovered. Conclusions: PCH1 is highly heritable and genetically correlated with SZ. It should prove useful in future genetic analyses. Mean PCH2 differentiates SZ families and controls but not SZ and unaffected family members.
PMID: 22234486 [PubMed - as supplied by publisher]
